Design, synthesis and anti-hepatic fibrosis activity of novel diphenyl vitamin D receptor agonists

Hepatic fibrosis poses a significant threat to human health due to excessive extracellular matrix (ECM) deposition leading to liver function damage. Ligand-activated vitamin D receptor (VDR) has been identified as an effective target for hepatic fibrosis, reducing ECM by inhibiting hepatic stellate cell (HSC) activation. Here, a series of novel diphenyl VDR agonists have been rationally designed and synthesized. Among these, compounds 15b, 16i, and 28m showed better transcriptional activity compared to sw-22, which was previously reported to be a potent non-secosteroidal VDR modulator. Moreover, these compounds exhibited outstanding efficacy to inhibit collagen deposition in vitro. In models of CCl₄-induced and bile duct ligation-induced hepatic fibrosis, compound 16i showed the most significant therapeutic effect by ultrasound imaging and histological examination. Moreover, 16i was able to repair liver tissue by reducing the expression levels of fibrosis genes and serum liver function indexes without causing hypercalcemia in mice. In conclusion, compound 16i is a potent VDR agonist with significant anti-hepatic fibrosis action both in vitro and in vivo.

Agonists; Diphenyl derivatives; Hepatic fibrosis; Hepatic stellate cells; Vitamin D receptor.